The present invention relates to a process which is useful in particular for converting the carbonyl function in position 4xe2x80x3of the cladinose unit of an aza-macrolide into an amine derivative.
The present invention relates more particularly to the field of erythromycin-type macrolide antibiotics and more particularly to the aza-macrolide derivatives thereof which form the subject of patent EP 508 699 and which correspond to the following general formula: 
in which R represents a hydrogen atom or a C1-C10 alkyl, C2-C10 alkenyl or C6-C12 arylsulphonyl group, which may be substituted.
These compounds are obtained from erythromycin and their synthesis involves two major steps:
the creation of the 8a-azalide macrocycle from the (Z) oxime which undergoes a stereospecific Beckmann rearrangement, and
the modification of the cladinose group in position 4xe2x80x3which consists in converting the 4xe2x80x3(S)xe2x80x94OH into 4xe2x80x3(R)xe2x80x94NH2, i.e. with inversion of configuration, which may be illustrated as follows: 
In point of fact, the route actually selected to carry out this conversion of the 4xe2x80x3(S)xe2x80x94OH function into 4xe2x80x3(R)xe2x80x94NH2 is not entirely suitable for industrial-scale production.
It involves, successively, an oxidation of the hydroxyl function in position 4xe2x80x3 into a ketone function and then conversion of this ketone into an oxime, which, on reduction, gives an approximately 1 to 1 mixture of the expected amine derivative and its 4xe2x80x3 epimer. The isomers obtained after this synthetic route are obtained in a low yield of about 20% and in addition are difficult to separate by chromatography. Thus, for a crude reaction yield of about 20%, only about 7% of the amine derivative with inversion of configuration is obtained.
The subject of the present invention is, precisely, to propose a novel route of access to these derivatives aminated in position 4xe2x80x3, in satisfactory yield.
More specifically, a subject of the present invention is described in the following numbered paragraphs:
1. Process for preparing a compound of general formula I 
in which:
R is a hydrogen atom or an optionally substituted C1-C10 alkyl, C2-C10 alkenyl or C6-C12 arylsulphonyl group, and
R1 and R2, which may be identical or different, represent
a hydrogen atom,
a C1-C10 alkyl group optionally substituted with one or more optionally substituted aryl groups, or an optionally substituted C6-C12 aryl group, by reductive amination of a compound of general formula II: 
in which:
R is as defined in the general formula I, and
P represents a hydrogen atom or a protecting group,
characterized in that it comprises:
placing the said compound of general formula II in contact with at least one nitrogenous reagent and a Lewis acid under conditions that are favourable for converting the 4xe2x80x3 carbonyl function,
reducing the resulting mixture using a reducing agent, and
optionally deprotecting the hydroxyl function in position 2xe2x80x2, to give the expected compound of general formula I.
2. Process according to paragraph 1, characterized in that the compound of general formula I is obtained in the form of a mixture of its 2 isomers 4xe2x80x3R and 4xe2x80x3S.
3. Process according to paragraphs 1 or 2, characterized in that the 4xe2x80x3R isomer is obtained as the major product.
4. Process according to one of the preceding paragraphs, characterized in that the nitrogenous reagent is chosen from ammonia, ammonium salts, for instance ammonium acetate or ammonium hydrochloride, primary amines NH2RA, secondary amines NH(RA)2 with the radicals RA, which may be identical or different, representing a C1 to C10 alkyl or C6 to C12 aryl group or a silyl group of the type SiRBRCRD in which the groups RB, RC and RD, which may be identical or different, can be an alkyl or aryl group.
5. Process according to paragraph 4, characterized in that the nitrogenous reagent is chosen from benzylamine, hexamethyldisilazane and ammonia.
6. Process according to one of the preceding paragraphs, characterized in that the nitrogenous reagent is introduced in a proportion of from 1 to 30 equivalents relative to the compound of general formula II and preferably in a proportion of from 1 to 10 equivalents.
7. Process according to one of the preceding paragraphs, characterized in that the Lewis acid is aprotic.
8. Process according to one of the preceding paragraphs, characterized in that the Lewis acid is introduced in a proportion of from 1 to 30 equivalents relative to the compound of general formula II.
9. Process according to one of the preceding paragraphs, characterized in that the Lewis acid is chosen from organometallic complexes of the elements from column IVB, IIIA or IIB of the Periodic Table of the Elements.
10. Process according to paragraph 9, characterized in that the said complex is chosen from titanium(IV) isopropoxide, aluminium(III) isopropoxide, titanium(IV) isopropoxide bis(acetylacetonate) and zinc(II) trifluoroacetate.
11. Process according to one of the preceding paragraphs, characterized in that the reducing agent is a metal hydride.
12. Process according to paragraph 11, characterized in that it is a boron or aluminium hydride.
13. Process according to paragraph 11 or 12, characterized in that it is sodium, lithium or zinc borohydride.
14. Process according to any one of the preceding paragraphs, characterized in that it is used in the presence of an organic solvent chosen from aromatic hydrocarbons, in particular toluene, halogenated solvents such as dichloromethane, alcohols such as methanol, nitrites such as acetonitrile, ethers such as THF or sulphoxides such as DMSO.
15. Process according to any one of the preceding paragraphs, characterized in that the Lewis acid is titanium isopropoxide or aluminium isopropoxide, the nitrogenous reagent is ammonia, hexamethyldisilazane or benzylamine, and the solvent is dichloromethane, tetrahydrofuran or toluene.
16. Process according to paragraph 15, characterized in that the reducing agent is sodium borohydride or lithium borohydride.
17. Process according to any one of the preceding paragraphs, characterized in that the compound of formula II dissolved in an organic solvent is added to the mixture of the Lewis acid and the nitrogenous reagent.
18. Process according to any one of paragraphs 1 to 16, characterized in that the compound of formula II and the Lewis acid are mixed together in an organic solvent and the nitrogenous reagent is added slowly to this mixture.
19. Process according to any one of paragraphs 1 to 16, characterized in that the compound of formula II is mixed with the nitrogenous reagent in an organic solvent and the Lewis acid is then added.
After the said process, the two isomeric forms R and Z of the expected 4xe2x80x3 amine derivative are obtained. However, the diastereoselectivity is such that the 4xe2x80x3R form is generally obtained predominantly. As emerges from the examples given below, the process claimed can advantageously give a 4xe2x80x3R/4xe2x80x3S mixture with a molar ratio from 60/40 and which may be up to 90/10.
Consequently, the process claimed is found to be particularly advantageous for obtaining this (4xe2x80x3R)-amino derivative, whose separation from the (4xe2x80x3S)-amino form obtained as the minor product can then be carried out by the techniques known to those skilled in the art.
In the context of the present invention, a compound of general formula II is thus reacted with a nitrogenous agent and a Lewis acid under conditions that are sufficient to allow the conversion of the carbonyl function in position 4xe2x80x3. When this conversion is complete, the resulting mixture is reduced directly to give the compound of general formula I.
The process claimed advantageously does not require an intermediate step and allows the two reactions to be carried out in sequence in the same reaction medium.
Nitrogenous reagents which can be used in particular include a compound chosen from ammonia, ammonium salts such as ammonium acetate, ammonium hydrochloride, primary amines NH2RA and secondary amines NH(RA)2 in which the radicals RA, which may be identical or different, represent a C1 to C10 alkyl or C6 to C12 aryl group or a silyl group of the type SiRBRCRD in which the groups RB, RC and RD, which may be identical or different, can be an alkyl or aryl group.
Benzylamine, ammonia and hexamethyldisilazane are most particularly suitable for the invention.
The nitrogenous reagent can be used in a proportion of from 1 to 30 equivalents relative to the compound of general formula II and preferably in a proportion of from 1 to 10 equivalents.
As regards the Lewis acid, it is preferably aprotic.
Lewis acids which are most particularly suitable include organometallic complexes of the elements from column IVB, IIIA or IIB of the Periodic Table of the Elements, and in particular those based on titanium, zinc and aluminium. The substituents on these complexes can be of alkoxy, acyloxy, sulphonate, halo, Schiff""s base or acetylacetonate type or a n-donor ligand such as cyclopentadienyl.
The following compounds are thus suitable for the invention: titanium(IV) isopropoxide, aluminium(III) isopropoxide, titanium(IV) isopropoxide bis(acetylacetonate), zinc(II) trifluoroacetate.
This Lewis acid can thus be used in a proportion of from 1 to 30 equivalents relative to the compound of general formula II and more preferably in a proportion of from 1 to 10 equivalents.
As discussed previously, the Lewis acid and the nitrogenous reagents are, in a first step, placed in contact with the compound of general formula II.
It is thus possible to react:
the Lewis acid and the compound of general formula II before introducing the nitrogenous reagent,
the Lewis acid and the nitrogenous reagent, followed by the compound of general formula II, or
the nitrogenous reagent, the compound of general formula II and the Lewis acid simultaneously.
Irrespective of the order selected for placing the reagents in contact, the reducing agent is added only once the conversion of the 4xe2x80x3 ketone function is complete.
Advantageously, the reaction medium is then reduced directly using a reducing agent.
Metal hydrides are most particularly suitable in the invention as reducing agent. Preferably, it is an aluminium or boron hydride and more preferably a substituted or unsubstituted boron hydride.
Substituted borohydrides which may thus be used are borohydrides mono-, di- or trisubstituted with:
mono- or dicarboxylic acids such as RCO2H in which R represents an optionally substituted alkyl or aryl group,
alcohols of the type ROH in which R is as defined above, or
1,2-, 1,3- or 1,4-diols and associated with a counter-cation, which is either of alkaline nature such as Li, Na or K, or of organic nature of quaternary ammonium type or alternatively of metallic type such as zinc, calcium or zirconium.
According to a preferred embodiment, the borohydride agent is different from a cyanoborohydride derivative.
Sodium, lithium and zinc borohydrides or sodium dibenzoyloxyborohydride are most particularly suitable for the invention.
The reducing agent is used in an amount which is sufficient to form the compound of general formula III: 
Generally, the amount used ranges from 1 to 10 equivalents and more preferably from 1 to 5 equivalents.
The entire process is generally carried out in an organic solvent.
This solvent can be chosen in particular from aromatic hydrocarbons such as toluene, halogenated solvents such as dichloromethane, alcohols such as methanol, nitrites such as acetonitrile, ethers such as THF and sulphoxides such as DMSO.
As regards the other reaction parameters, i.e. reaction temperature and reaction time, their adjustment falls within the competence of a person skilled in the art. The reaction can thus be carried out at a temperature of between xe2x88x9230xc2x0 C. and the reflux point of the solvent and this reaction temperature can vary in the course of the reaction.
As regards the compound of general formula II, it is generally obtained beforehand starting from the compound of general formula IV: 
by protecting the hydroxyl function in position 2xe2x80x2 of the said compound, followed by oxidation of the hydroxyl function in position 4xe2x80x3.
The protection is carried out conventionally using a conventional protecting group for a hydroxyl function, such as those featured in xe2x80x9cProtective groups in organic synthesisxe2x80x9d Second Edition, Theodora W. Greene, P. G. Wuts, Wiley Intersciences, pp. 10-142. The procedures for carrying out the protection and deprotection operations are also described in the book referred to above.
As regards the oxidation, it can be carried out according to the procedure described in EP 508 699.
After the reduction according to the process claimed, deprotection of the function at 2xe2x80x2 is thus carried out, if necessary.
According to preferred variants of the invention, titanium isopropoxide or aluminium isopropoxide is used as Lewis acid. As regards the associated nitrogenous reagent, it is preferably chosen from ammonia, hexamethyldisilazane and benzylamine. Under these conditions, the solvent used is preferably chosen from dichloromethane, tetrahydrofuran and toluene.
The preferred reducing agent is sodium borohydride or lithium borohydride.
According to a first variant of the invention, the compound of the formula II dissolved in an organic solvent, preferably toluene or dichloromethane, is added to a mixture of the Lewis acid such as titanium(IV) isopropoxide or aluminium(III) isopropoxide with the nitrogenous reagent, such as benzylamine, hexamethyldisilazane or ammonia, and the assembly is kept stirring at room temperature and optionally heated to the reflux point of the reaction medium.
In a second variant, the Lewis acid, such as titanium(IV) isopropoxide is placed in contact with the compound of formula II in an organic solvent such as THF or toluene, followed by slow addition of the nitrogenous reagent, preferably hexamethyldisilazane. The assembly is kept stirring at room temperature and optionally heated to the reflux point of the reaction medium.
According to a third variant, the compound of general formula II is mixed with the nitrogenous reagents, preferably ammonia, in an organic solvent. The Lewis acid, preferably titanium diisopropoxide bis(acetylacetonate) dissolved in the same organic solvent, is then added thereto and the assembly is kept stirring at room temperature and optionally heated to the reflux point of the reaction medium.
Irrespective of the variant considered, the reduction is carried out consecutively by adding the reducing agent directly into the reaction medium. The reduction is allowed to go to completion, followed by hydrolysis of the reaction medium and then at least one extraction.
If necessary, the compound of general formula III is then deprotected so as to obtain the compound of general formula I, which is then isolated according to a conventional procedure which generally involves extraction, washing and then drying operations.